Gastrointestinal (GI) dysmotilty is a significant cause of morbidity in diabetic patients, but the patho-physiology of this complication has not been established. Autoimmunity is the basis of juvenile diabetes and may account for 10% of adult-onset diabetes. Patients with autoimmune diabetes are predisposed to other manifestations of organ-specific autoimmunity. We propose to test the hypothesis that diabetic GI dysmotility results from autoimmune disruption of the intrinsic and/or extrinsic enteric nervous system. This hypothesis is based on 1) reports that several neuronal and muscle autoantibodies serve as markers of autoimmune GI dysmotility and 2) our discovery that IgG specific for ganglionic neuronal acetylcholine receptor (AChR, a critical mediator of fast synaptic transmission in autonomic and enteric ganglia) is both a marker and cause of severe GI hypomotility. We have developed animal models of autoimmune GI dysmotility by active immunization with ganglionic AChR protein and by passive transfer of ganglionic AChR-specific IgG. We propose to characterize and compare two mouse models of autoimmune GI dysmotility with spontaneous GI dysmotility in the diabetic NOD mouse, looking for common immuno-histopathological and electrophysiological features. We will investigate the mechanism of lgG-meditated GI dysmotility in detail in conventional mice and determine whether NOD mice exhibit heightened sensitivity to IgG-mediated dysmotility. In parallel serological studies, we will determine the frequency of neuronal and other organ-specific autoantibodies in diabetic patients with dysmotility, searching in particular for novel enteric nervous system-specific antibodies. We will also investigate in mice the effects on GI motility of injecting human IgG containing novel enteric autoantibodies. Our project will combine both animal and human studies to elucidate whether or not autoimmunity is involved in diabetic dysmotility, what mechanism are involved in IgG-mediated dysmotility and whether serum autoantibody profiles might aid the diagnosis of autoimmune GI dysmotility and justify immunomodulatory therapy.